Background: Craving has been identified as a precipitant of relapse to drinking in sober alcoholics. Despite the extensive efforts to reduce craving for alcohol through pharmacologic treatments for alcoholism, there is a virtual absence of studies of the clinical neurobiology of craving. This proposal bill attempt to provide insights to the neurobiology of alcohol craving through studying craving induced in the laboratory by exposure to alcohol. Objectives: Phase I: To determine whether cerebrospinal fluid levels of the norepinephrine metabolite, MHPG, or the serotonin metabolite, 5-HIAA, predict the magnitude of subsequent alcohol cue-induced craving. Phase II: To determine whether an intervention designed to reduce plasma tryptophan levels by over 90%, resulting in approximately a 40% reduction in brain serotonin levels, reduces the magnitude of alcohol cue-induced craving. Methods: Phase I. In an ongoing study, inpatients in a rehabilitation program meeting DSM-III-R criteria for alcohol dependence and von Knorring criteria for early onset (type II) alcoholism will be recruited, 1-3 months post-detoxification. Patients will complete lumbar puncture and, after 3 days, will complete an initial alcohol cue exposure session. Phase II: Patients exhibiting at least a 20% increase in craving in the initial cue exposure session will complete two additional cue-exposure tests. Cue exposure sessions will be preceded by placebo (tryptophan supplemented) or active(no tryptophan supplementation) tryptophan depletion. Tryptophan depletion will be achieved by giving an amino acid load devoid of tryptophan, causing increased utilization of remaining plasma tryptophan. Each test day will be scheduled one week apart, and the sequence will be randomized. Preliminary Results: Preliminary results indicate a significant correlation between CSF MHPG levels and subsequent cue-induced craving. 5-HIAA showed non-significant correlation. Tryptophan depletion appeared to reduce cue-induced craving for alcohol. Implications: These data may support a heuristic model, described in this application, in which noradrenergic and serotonergic differentially contribute to the modulation of cue-induced craving. Noradrenergic systems are proposed to modulate the arousal reactivity, while serotonergic systems modulate more specifically the processing of ethanol-like cues.